CCR2 Inhibitor Plus FOLFIRINOX Shows Promise For Early-Stage Pancreatic Cancer

CCR2 Inhibitor Plus FOLFIRINOX Shows Promise For Early-Stage Pancreatic Cancer

Preliminary research points to a potential role for CCR2 inhibition in the treatment of borderline resectable and locally advanced ductal adenocarcinoma of the pancreas

Date: 05 Apr 2016
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Drug Development / Pancreatic Cancer
medwireNews: A novel agent targeting the CCL2–CCR2 chemokine axis may have promise as an neoadjuvant treatment alongside chemotherapy in patients with borderline resectable and locally advanced pancreatic cancer, suggest early trial findings indicating the inhibitor to be well tolerated.

“No neoadjuvant therapy currently provides a durable clinical effect in patients with pancreatic ductal adenocarcinoma”, observe David Linehan, from the University of Rochester Medical Center in New York, USA, and co-workers.

“CCR2 inhibition is a promising therapeutic strategy and should be explored in further clinical trials.”

The open-label phase 1b trial included a total of eight treatment-naïve patients given six cycles of FOLFIRINOX and 39 patients who received chemotherapy alongside PF-04136309, an oral small molecule CCR2 inhibitor.

Just one of the patients given PF-04136309 at the starting dose of 500 mg twice daily required dose reduction; the 500 mg twice daily dose was thus fixed as the recommended dosing for phase II studies, say the researchers.

Six of the eight FOLFIRINOX-only patients and 39 of the combined treatment patients were followed-up for toxicity for a median of 72 and 77 days, respectively.

Two patients given PF-04136309 terminated treatment early due to treatment-related toxicity, with grade 3 or more serious events occurring in at least 10% of the group including neutropenia, febrile neutropenia, lymphopenia, diarrhoea and hypokalaemia.

Similarly, grade 3 or above neutropenia, febrile neutropenia, anaemia, lymphopenia, diarrhoea, hypoalbuminaemia and hypokalaemia were reported in at least 10% of patients given FOLFIRINOX only, one of whom ended treatment early.

“In summary, PF-04136309 in combination with FOLFIRINOX did not result in additional toxicity at the recommended phase 2 dose”, the team writes in The Lancet Oncology.

Moreover, repeated imaging in 33 of the patients given chemotherapy plus PF-04136309showed that 48.5% had a partial response, a significantly higher rate than the prespecified expectation of 25.0% for FOLFIRINOX alone, the authors observe.

And 97% of the 33 patients achieved at least local tumour control, with just one patient experiencing disease progression and no reports of distant metastases.

By contrast, none of the five FOLFIRINOX-only patients assessed for efficacy achieved an objective treatment response; four had stable disease and one patient had distant metastases.

David Linehan et al report that lesion size reduced sufficiently to allow surgery in 39% of the 33 patients given the combined treatment. Seven of 10 patients who underwent resection achieved an R0 outcome and five had negative lymph nodes; six patients underwent additional neoadjuvant radiotherapy and chemotherapy.

Of note, patients who received FOLFIRINOX alone experienced an average 68.20% decrease in CCR2-positive monocytes in their bone marrow after treatment and a mean 42.67% increase in CCR2-positive monocytes in their blood samples.

By contrast, after PF-04136309 plus FOLFIRINOX treatment, patients had a 66.43% increase in bone marrow CCR2-positive monocytes and a 36.56% decrease in circulating CCR2-positive monocytes.

“FOLFIRINOX plus PF-04136309 prevented CCR2-positive monocyte egress from the bone marrow to the peripheral blood and reduced tumour-associated macrophage infiltrate at the primary tumour”, the researchers propose.

“The subsequent reversal of immune suppression within the tumour microenvironment, and the influx of tumour-infiltrating lymphocytes, suggests a restoration of anti-tumour immunity.”

Noting that this effect was strongest in patients who achieved a RECIST objective response, the authors suggest that “[a]lthough interpretation of this finding is limited by the small study population, this Biomarker evidence suggests that the clinical activity seen with FOLFIRINOX plus PF-04136309 correlated with target engagement.”

They conclude: “Our results support a potential therapeutic effect of use of targeted therapy to disrupt the CCL2–CCR2 chemokine axis in pancreatic ductal adenocarcinoma.”

Reference

Nywening TM, Wang-Gillam A, Sanford DE, et al. Targeting tumour-associated macrophages with CCR2 inhibition in combination with FOLFIRINOX in patients with borderline resectable and locally advanced pancreatic cancer: a single-centre, open-label, dose-finding, non-randomised, phase 1b trial. Lancet Oncol 2016; Advance online publication 4 April. http://dx.doi.org/10.1016/S1470-2045(16)00078-4